Diffuse large B cell lymphoma (DLBCL) is the most common form of non Hodgkin lymphoma, with an annual incidence of 25,000 in the United States and nearly 10,000 deaths per year attributable to the disease. Although chemotherapy is the mainstay of therapy, there has been no improvement in the chemotherapy regimens used to treat DLBCL in the past 30 years. The addition of rituximab to standard chemotherapy has been a significant advance in the treatment of the disease. However, only about 50% of patients with this disease are cured after treatment with chemotherapy and rituximab. There have been over 60 clinical trials in patients with DLBCL that have demonstrated no benefit. An important reason for the failure of many clinical trials in DLBCL may be the approach to the disease as a single entity, even though it is known to be molecularly heterogeneous. Gene expression profiling of patients with DLBCL demonstrated that the tumors comprised at least two distinct diseases with different cells of origin, distinct cytogenetic differences and different response rates to anthracycline-based chemotherapy regimens. In this proposal, we demonstrate how the molecular subclassification of DLBCL reveals new tumor-susceptibilities that can be explored in the clinic. PUBLIC HEALTH RELEVANCE: Molecular profiling has provided new opportunities for unraveling tumor biology by the enumeration of differentially expressed genes and oncogenic pathways. In diffuse large B cell lymphoma, the most common form of lymphoma, molecular profiling has demonstrated that the diagnosis comprised at least two molecular subgroups that are dramatically different with regard to their gene expression profile as well as to standard combinations of chemotherapy. We propose a novel approach using the molecular subclassification of diffuse large B cell lymphoma to identify new therapeutic targets that are most likely to be effective in the molecularly defined groups of patients.